Abstract 11904: Lipoprotein(a) Integrates Monocyte-Mediated Thrombosis and Inflammation in Atherosclerotic Cardiovascular Disease

Introduction: Lipoprotein (a) [Lp(a)] drives atherosclerotic cardiovascular disease (ASCVD) through multiple mechanisms including cholesterol accumulation, inflammation, and thrombosis. However, the effects of Lp(a) on monocyte activation and monocyte-mediated thrombosis are unknown. Hypothesis: Lp(a) itself can activate monocytes, driving inflammation and thrombosis in parallel. Methods: We employed systems biology approaches consisting of proteomics, transcriptomics, and mass cytometry to define the immune cellular and molecular phenotypes in ASCVD subjects with high and low Lp(a) levels and leveraged cell models to define the mechanisms through which Lp(a) drives monocyte inflammation and thrombosis. We included study participants with CHD who were aged 18 to 80 years with Lp(a) concentrations > 150 nmol/L (cases) and <75 nmol/L (controls). Results: Circulating markers of inflammation (CCL3, CD40) and vascular dysfunction (PAR1, tissue factor [TF]) were elevated in subjects with high Lp(a) levels compared with those with low Lp(a) levels. Additionally, although total monocytes levels and hs-CRP levels were similar between the groups, CD14+ monocytes from ASCVD subjects with an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress. Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptors (TLR) and nuclear factor kappa B (NFκB) signaling, driving both TF expression and TF activity (Figure). Conclusions: Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis in ASCVD subjects, demonstrating a novel mechanism through TLR2, NFκB, and monocyte TF through which Lp(a) amplifies immunothrombotic risk.